The present invention relates to compositions including recombinant adeno-associated vectors (AAVs) comprising genes to be expressed in skeletal and cardiac muscle tissue, as well as methods for treatment of muscular defects.
Duchenne's muscular dystrophy (DMD) is a severe X-linked muscle degenerative disease caused by the absence of the cytoskeletal protein dystrophin. The dystrophin protein provides stability to the sarcolemma (i.e., the cell membrane of muscle cells) by linking the intracellular cytoskeletal network to the extracellular matrix. In the absence of dystrophin, muscle contraction mechanically stresses the cell membrane, inducing progressive damage to the myofibers. Initially, skeletal muscles are predominantly affected; however, as the disease progresses, the damage extends to cardiac muscle and death is caused by respiratory or cardiac failure. DMD is one of the most common genetic diseases, affecting an estimated 1 out of every 3,600 male births each year. DMD is a debilitating disease that progressively worsens over the short (approximately 25 year) lifespan of those affected. Unfortunately, despite years of research, there are no curative treatments for muscular dystrophies including DMD. Current therapies are limited to managing symptoms.
Gene transfer by recombinant AAV has gained increasing value in recent years for experimental and human gene therapy. AAVs are small viruses that elicit a very mild immune response and do not cause any known human diseases. Additional advantages of these viral vectors include the existence of several serotypes ensuring a wide spectrum of tissue-specific tropism, as well as a robust, long-term transgene expression in vivo. Many successful preclinical studies on animal models have paved the way for the use of recombinant AAV-based gene delivery for clinical applications. However, the extremely large size of the dystrophin gene (approximately 2,400 kilobases or kb) has complicated efforts for gene therapy to treat DMD or related dystrophinopathies, because the packaging size of inserts into recombinant AAV vectors is limited to about 4.7 kb.
Therefore, a need exists for improved muscle-specific recombinant AAV vectors for delivery of genes to both skeletal and cardiac muscle. There also exists a long-standing need for compositions and methods for treating muscular dystrophies, especially DMD.